Abstract

Focused ultrasound (FUS) with the presence of microbubbles induces blood brain barrier (BBB) opening in targeted areas and facilitates drug delivery. However, recent studies have indicated that FUS-BBB opening with excessive exposure levels may be associated with inflammatory response and cellular/tissue damage. Multiple weekly FUS exposures have been shown to be safe for human subjects. However the effect of more frequent FUS exposures is still unknown. This study examines whether frequent focused ultrasound blood brain barrier opening is associated with aggravated behavioral, histopathologic change or brain tissue damage. Two protocols of focused ultrasound blood brain barrier opening were devised using different microbubble doses (0.15 µl/kg and 0.4 µl/kg). Focused ultrasound exposure at a threshold level of BBB-opening, below-threshold level, or above level for intracerebral hemorrhage were delivered every 2 days. Animal behavioral and physiological changes were examined and recorded. Brain tissue was examined for hemorrhage and apoptosis. Results indicate that frequent exposure of excessive focused ultrasound (1.4 mechanical index) produced minor and short-term behavioral changes despite significant tissue damage, while frequent BBB opening with threshold or below-threshold FUS exposure (0.33–0.8 mechanical index) did not cause behavioral or histological change. Immunofluorescent examination of rat brain tissue indicated that excessive doses of microbubble administration induce an apparent cellular apoptotic response, which may be exacerbated by intracerebral hemorrhage. Experimental results suggest that frequent focused ultrasound blood brain barrier opening with sufficient ultrasound exposure level and a microbubble dose can be safe and pose minimal risk to brain tissue.

Highlights

  • The blood brain barrier (BBB) poses significant impediments to the treatment of malignant glioma of the brain[1]

  • We found that the BBB-opening threshold for the excessive MB group was 0.33-mechanical index (MI), while 0.8-MI caused significant intracerebral hemorrhage

  • We examined the behavior of SD rats subjected to repeated focused ultrasound (FUS)-BBB opening at exposure levels of 0.47-MI, 0.8MI, and 1.4-MI

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Summary

Introduction

The blood brain barrier (BBB) poses significant impediments to the treatment of malignant glioma of the brain[1]. Some recent reports indicate that application of FUS capable of disrupting the BBB may cause cellular apoptosis or sterile inflammation in the target tissue[22,23], raising concerns about the safety of such a treatment modality These studies only performed single exposures, or were repeated weekly or biweekly to allow for tissue recovery or remodeling. Previous glioma animal experiments have shown that FUS-BBB opening every other day as an adjunct to TMZ chemotherapy increased drug concentrations in the target area, improved tumor growth inhibition, and increased overall survival[17,18]. The safety of such frequent and repeated BBB-openings is still unclear

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